tbuckley/cabot-search huggingface dataset:
Pazopanib in metastatic soft tissue sarcoma (STS): Results of a multi-institutional observational study.
Authors: Ahmet Bilici, Sinan Koca, Mustafa Karaagac, Emrah Eraslan, Birol Ocak, Sabin Goktas Aydin, Sema Sezgin Goksu, Semra Paydas, Sumeyye Derin, Yakup Ergun, Emre Yekegunduz, Cihan Erol, Deniz Tataroglu Ozyukseler, Atike Gokcen Demiray, Mustafa Karaca, Zeynep Gulsum Guc, Serkan Menekse, Havva Yesil Cinkir, Ozge Gumusay, Abdullah Sakin
Journal: Journal of Clinical Oncology (2022)

e23542 Background: Soft tissue sarcomas (STS) are a heterogenous group of tumors which have limited therapeutic options and poor prognosis in advanced/metastatic settings. Herein, we present the clinical outcomes of metastatic STS patients treated with pazopanib (PAZ) in real-life. Methods: We retrospectively collected data about adult patients treated with PAZ for metastatic STS in Turkey. We described the clinical characteristics and tumor responses, and estimated the progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. The Cox proportional hazards regression model (HR, 95%CI) was used for evaluation of prognostic factors for PFS. Results: 507 patients (median age: 52 [range: 18-87]; 56.8% female) were included in the analysis. Extremities were the most common primary tumor sites (n:202; 39.8%) followed by abdomen (n:116; 22.9%) and pelvic cavity (n:102;20.1%) where 98% of STSs arose in uterus (n:100). The leading histologic subtypes were leiomyosarcoma (n:192; 37.9%), synovial sarcoma (n:58; 11.4%) and undifferentiated pleomorphic sarcoma (n:48; 9.5%). Of the reported tumor grades (n = 350), 61.4% (n:215) were grade 3. The most common metastatic sites were lungs (52.7%) and liver (20.3%). Doxorubicin plus ifosfamide (45.9%) was the preferred front-line regimen and PAZ was the treatment of choice in second (59.8%) and third-line (61.8%) settings. The median follow-up under PAZ treatment was 5.03 (0.10-84.67) months. Objective response and disease control rates were 31.4% and 42.2%, respectively. Overall, 183 (36.1%) patients were alive at last follow up, 123 of which (67.2%) did not show progression. The median PFS and OS for the study group and the most commonly observed types of STS are shown in Table. Favorable prognostic factors for PFS were low-intermediate tumor grade (HR[95% CI] for grade I and 2 vs 3:1.371[1.016-1.849]; p = 0.039) and ECOG (Eastern Cooperative Oncology Group) score (HR[95% CI] for ECOG score &lt; 2 vs ≥2: 2.698[1.923-3.787]; p = 0.0001). Weakness/asthenia (10.8%), impaired liver function tests (4.7%) and diarrhea (3.6%) were the most common adverse events, no grade 4 or 5 events were observed. Conclusions: This large scale real-life study confirms that PAZ, with its positive impact on clinical outcomes and acceptable tolerability and safety profile is a valuable treatment option for metastatic STS.[Table: see text]
Chemotherapy shows better efficacy than endocrine therapy in patients with metastatic breast cancer with heterogeneous estrogen receptor expression.
Authors: Yizhao Xie, Xinyue Du, Zhonghua Tao, Yannan Zhao, Chengcheng Gong, Xichun Hu, Zhongyi Yang, Biyun Wang
Journal: Journal of Clinical Oncology (2022)

1050 Background: Heterogeneity of estrogen receptor (ER) expression has long been challenges for diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient way of ER detection using 18 F-fluoroestradiol positron emission tomography/computed tomography ( 18 F-FES PET/CT) offers a chance to screen and analyze MBC patients with ER uncertainty. Methods: MBC patients who received 18 F-FES PET/CT were screened and patients with both FES positive (FES+) and negative (FES-) lesions were enrolled in this study. Progression‐free survival (PFS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: A total of 635 patients were screened and 75 of 635 (11.8%) patients showed ER uncertainty. 51 patients received further treatment and were enrolled in this study. Among them, 20 (39.2%) patients received chemotherapy (CT), 21 (41.2%) patients received endocrine-based therapy (ET) and 10 (19.6%) patients received combined therapy (CT+ET). CT showed better progression-free survival (PFS) compared to ET (mPFS 7.1 vs 4.6 months, HR 0.44, 95% CI 0.20-0.93, P = 0.03). CT+ET did not improve PFS compared to either CT or ET alone (mPFS 4.4 months, P &gt; 0.2). Conclusions: 18 F-FES PET/CT could identify patients with ER heterogeneity. Patients with ER uncertainty showed better sensitivity to CT rather than ET. Combined therapy of CT+ET did not improve treatment outcome.
A prospective comparative and functional analysis of different ablative techniques for MRI/real-time ultrasound image fusion guided High Intensity Focused Ultrasound (HIFU)
Authors: S. De Luca, E. Checcucci, F. Piramide, D. Amparore, G. Volpi, S. De Cillis, A. Piana, P. Alessio, A. Pecoraro, M. Sica, P. Verri, S. Granato, M. Burgio, L. Ola, A. Quarà, M. Manfredi, C. Fiori, F. Porpiglia
Journal: European Urology (2022)
Transition for transduction: how to make cardiac endothelial cells more permissive to AAV
Authors: N Volf, N Ring, A Colliva, R Vuerich, L Braga, L Zentilin, S Zacchigna
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Despite major attempts aiming to revascularize an ischemic heart, prognosis of cardiac ischemia remains poor. A major obstacle for the induction of new blood vessels, referred as therapeutic angiogenesis, is inefficient gene transfer in cardiac endothelial cells (ECs). This poor permissiveness to genetic modification is a limiting step in studies of pathological conditions with inadequate, but also with increased vascularization. To study the function of a specific gene and its potential implications in angiogenesis, the most straightforward approach would be to either overexpress or silence it in ECs. We and others have tested multiple protocols for either transfection and transduction of primary ECs in vitro and in vivo, with no success. Vectors based on Adeno-associated virus (AAV) and Lentivirus (LV) stand as ideal tools for gene delivery, however they do not work in cardiac ECs. Purpose To enhance the permissiveness of EC, we optimized and performed high-throughput screening on adult cardiac ECs using a library of FDA approved drugs, to search for compounds increasing transduction by AAV6 and LV, with the final aim to identify the major determinants inhibiting genetic modification of ECs. Methods Cardiac ECs were isolated from 2 months old C57BL/6 mice and plated on 384-well plates. After 48 hours, the FDA drug library (&amp;gt; 1500 compounds) was added together with AAV6-dsRed and LV-GFP. Cells were fixed with 4% PFA 72 hours post-transduction, and subsequently stained for the EC marker ERG. The levels of AAV6-dsRed, LV-GFP and ERG expression were assessed by automated, high-content microscopy. Results After two rounds of screening at different drug concentrations, we obtained a list of candidate compounds able to increase adult cardiac EC transduction by either AAV6 or LV over two folds. Among these, our best hit increasing AAV6-mediated transduction was Vatalanib, a tyrosine kinase inhibitor acting on VEGFRs, PDGFR, and c-Kit. Valatanib not only increased permissiveness to AAV6, but it also changed the morphology of the cells, which became elongated and similar to mesenchymal cells. This suggested ongoing endothelial mesenchymal transition (EndMT), which was verified by decreased CD31 and increased α-SMA expression. Interestingly, AAV mostly transduced cells with the lowest CD31 expression. Conclusions Our high-throughput screening identified Vatalanib as the most potent drug in increasing permissiveness of cardiac ECs to AAV transduction. Because the drug induced loss of CD31 and gain in α-SMA, we hypothesized that the reason for increased permissiveness was EndMT. This hypothesis is consistent with the known mechanism of action of Valatanib, which inhibits VEGFR2 and thus interferes with VEGF signalling, that in turn is essential to maintain EC identity.
A phase Ib/II study of the combination of lenvatinib (L) and eribulin (E) in advanced liposarcoma (LPS) and leiomyosarcoma (LMS) (LEADER): Efficacy updates.
Authors: Tom Wei-Wu Chen, Chueh-Chuan Yen, Ruey-Long Hong, Jen-Chieh Lee, Koping Chang, Chih-Wei Yu, San-Chi Chen, Mei-Lu Chen, Meng-Chi Hsu, Ting-Fang Kung, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2022)

11506 Background: There are limited treatment options for advanced LPS and LMS, the two most common histologies in soft tissue sarcoma. Patients (pts) treated with E had an improved overall survival (OS) compared to dacarbazine but with an unsatisfactory 4% objective response rate (ORR). Early studies of L, a multi-targeted anti-angiogenic inhibitor, had suggested efficacy in sarcoma pts. We hypothesized that the L+E could potentiate the treatment efficacy in advanced LMS and LPS. Methods: LEADER was a single-arm phase Ib/II study for advanced adult LMS and LPS pts who had received no more than 2 lines of systemic chemotherapy (NCT03526679). The phase Ib part (starting dose: L 18mg/day, E 1.1mg/m 2 ) had been reported and the recommended phase 2 dose (RP2D) was determined at L 14mg/day and E 1.1mg/m 2 D1, D8 every 21 days. The primary endpoint of the phase II part was ORR by RECIST 1.1, secondary endpoints included progression-free survival (PFS), 6-month PFS rate, and OS. Pts in phase Ib/II part were analyzed together for efficacy. Results: As of Nov 15 2021, 30 pts (F/M 20/10) had been treated with at least one cycle of L + E; 21 were LMS (9 uterine, 12 non-uterine) and 9 were LPS (5 dedifferentiated, 2 myxoid round cell, 2 pleomorphic). The median age was 59 (range 29-73); the median lines of treatment(s) received before enrollment was 1 (range 0-3). The ORR by RECIST 1.1 was 20 % (6/30) (95% CI 10-53%); the ORR for pts received L 18mg/day (2/6) and L 14mg/day (4/26) were not significantly different (p = 0.23). After a median FU time of 20.1 months, the median PFS and 6-month PFS rate was 8.56 mos (95% CI 4.40-not reached (NR)) and 59%, respectively. The median PFS for LMS (8.56 mos, 95% CI 4.17- NR) and LPS (11.36 mos, 95% CI 4.4-NR) were not significantly different (p = 0.73). The median OS and 12-month OS rate was 26.2 mos (95% CI 21.4-NR) and 89%, respectively, but LPS pts had significantly worse OS (HR 3.5, p = 0.04). Twenty pts experienced at-least one grade (gr) 3 or 4 adverse event (AE); gr 3 or 4 AEs occurred in &gt; 1 pt included hypertension (n = 4); hand-foot-syndrome (HFS) (n = 5), proteinuria (n = 3), febrile neutropenia (n = 3), neutropenia (n = 11, without G-CSF support). Compared to L 18mg/day, pts treated with RP2D were associated with lower gr3/4 HFS and hypertension. There were no sustained grade 3/4 AEs for pts receiving long-term L+E. Conclusions: L + E had shown promising efficacy in advanced LMS and LPS. L at 14mg (vs 18mg) had a better AE profile without compromising activity. Future randomized study to confirm the efficacy of the combination is warranted. Clinical trial information: NCT03526679.
Effectiveness, immunogenicity, and safety of COVID-19 vaccines for individuals with hematological malignancies: a systematic review
Authors: Vanessa Piechotta, Sibylle C. Mellinghoff, Caroline Hirsch, Alice Brinkmann, Claire Iannizzi, Nina Kreuzberger, Anne Adams, Ina Monsef, Jannik Stemler, Oliver A. Cornely, Paul J. Bröckelmann, Nicole Skoetz
Journal: Blood Cancer Journal (2022)

The efficacy of SARS-CoV-2 vaccination in patients with hematological malignancies (HM) appears limited due to disease and treatment-associated immune impairment. We conducted a systematic review of prospective studies published from 10/12/2021 onwards in medical databases to assess clinical efficacy parameters, humoral and cellular immunogenicity and adverse events (AE) following two doses of COVID-19 approved vaccines. In 57 eligible studies reporting 7393 patients, clinical outcomes were rarely reported and rates of SARS-CoV-2 infection (range 0-11.9%), symptomatic disease (0-2.7%), hospital admission (0-2.8%), or death (0-0.5%) were low. Seroconversion rates ranged from 38.1-99.1% across studies with the highest response rate in myeloproliferative diseases and the lowest in patients with chronic lymphocytic leukemia. Patients with B-cell depleting treatment had lower seroconversion rates as compared to other targeted treatments or chemotherapy. The vaccine-induced T-cell response was rarely and heterogeneously reported (26.5-85.9%). Similarly, AEs were rarely reported (0-50.9% ≥1 AE, 0-7.5% ≥1 serious AE). In conclusion, HM patients present impaired humoral and cellular immune response to COVID-19 vaccination with disease and treatment specific response patterns. In light of the ongoing pandemic with the easing of mitigation strategies, new approaches to avert severe infection are urgently needed for this vulnerable patient population that responds poorly to current COVID-19 vaccine regimens.
JAMA Internal Medicine
Authors: Thomas Easley, Brian Shields, Karen Adams-Taylor, Paul Gee, Monica Smith, Jeff Ery, J Bonistalli, Kathy Russell, Mirna Monal, Stacey Mchugh, Tim Melroy, Marketing Thornbury, Tricia Castellano, Anna Coordinator, Meghan Thue, Sade Deramus-Townsend, Thalia Recruitment, Samantha Bauer, Hank Eurich, Marsha Fogler, Rachel Sisholtz, Saskia Bolore, Gretchen Linder, Brian Mccartney, Christine Hearne, Natasha Staff, Henry Aguillon, David Baum, Ron Marketing, Rick Bell, Elizabeth Solaro, Sara Zimmerman, Geoff Rey, Lindsay Dawson, Ellen Gibson, Craig Mccaff Rey, Michael Mcgraw, Daniel Pickhardt, Romando Rossini, Sarah Subramanian, Stacy Tucker, Walsh Business, Analyst Sirisha, Alluri Staff, Millette Jackson-Bates, Tom Miller, Jacob Mishkin, Morgan Business, Karl Elvin, Nancy Essex, Jaye Mize, Sean O'donnell, Sue Managers, David Antos, Anthony Bautista, Chris Borden, Debbie Camp, Lydia Cruz, Scott Curl, Diane Darnell, Nanette Diaz, Jordynn Farrar, Allison Hughes, Colleen Kelly, John Lash, Chris Meyer, Annemarie Neff, J Neff, Sean Ohlson, Phil O'leary, Bill Pedone, Susan Price, Jaynam Shah, Erin Spencer, Denise Steinhauser, Joe Advertising, Production Services, Ahmed Avendano, Kim Boler, Rhonda Brown, Fin Carter, Michael Deegan, Euwanaha Joiner-Smith, Joshua Lane, Cindy Rendlen, John Rhead, Janis Trinchere, Annissa Zak, Circulation Services, Julie Burton, Ronna Hewitt, Mary Sieck, Geneine Someren, Jamaal Vargas, Content Systems, Mike Bujewski, Nathan Mitre, Digital Production, Regina Brownlee, Amanda Camino, Brenda Chandler-Grayer, Emily Dunn, Amy Evers, Maleeka Holden, Teri Hutchison, Dan Knowles, Joshua Lampinen, Natalie Marsh, Patricia Panek, Marla Seidell, La Son Diggs-Sledge, Julian Graphics, Joe Amft, Jonathan Chala, James Collver, Maria Duda, Fred Furtner, Carolyn Hall, Maria Kowalkowski, Proofreading Carol, Joy Farrell, Maria Giannini, Sasha Grossman, Kate Lander, Judith Literskis, Teresa Omiotek, Michael Ryder, James Madara, Terri Carter, Fellows Mithi, Del Rosario, Vinay Guduguntla, Anand Habib, Audrey Han, Natalie Richmond, Eric Ward, Zachary Goldberger, Nora Goldschlager, San Francisco, Elsayed Soliman, Winston-Salem North, Fiona Clement, Rita Redberg, Deborah Grady, Michael Incze, Salt City, Tanner Caverly, Ann Arbor, Brandon Combs, Sanket Dhruva
Journal: JAMA Internal Medicine (2022)

Mission Statement: To promote the art and science of medicine and the betterment of public health by publishing manuscripts of interest and relevance to internists practicing as generalists or as medical subspecialists.
Trends in stage I lung cancer.
Authors: Aashray Singareddy, Mary Ellen Flanagan, Pamela Parker Samson, Saiama Naheed Waqar, Siddhartha Devarakonda, Jeffrey P. Ward, Brett Herzog, Anjali Rohatgi, Clifford Grant Robinson, Ramaswamy Govindan, Varun Puri, Daniel Morgensztern
Journal: Journal of Clinical Oncology (2022)

10508 Background: The American Cancer Society has recently reported an increase in the percentage of patients with localized lung cancer from 2004 to 2018 with a corresponding improvement in survival for all patients combined. We analyzed the recent trends in stage distribution for lung cancer including tumor and demographic factors. Methods: We selected patients with lung cancer from the National Cancer Database (NCDB) public benchmark report diagnosed between 2010 and 2017. Patients with unknown stage were excluded. Stage distribution using the AJCC 7 th edition of the TNM system was evaluated according to year of diagnosis, histology, age, gender, race, insurance and income. Results: Among the 1,447,470 patients from 1,384 hospitals identified in the database, 56,382 (3.9%) were excluded due to unknown stage or incorrect histology, leaving 1,391,088 patients eligible. The percentage of patients with stage I progressively increased from 23.5% in 2010 to 29.1% in 2017 while stage IV decreased from 45.5% to 43.1% during the same period (Table). The increased in percentages of stage I from 2010 to 2017 were 25.9% to 31.8% in non-small cell lung cancer (NSCLC) and 5.0% to 5.4% in small cell lung cancer (SCLC). Although the increased percentage of stage I lung cancer was observed in all subsets of patients, there were significant imbalances according to demographic and socio-economic factors. In the year 2017, the major gaps in stage I included insurance (31.4% for Medicare, 26.4% for private insurance, and 12.9% for uninsured), income (32.4% for the highest annual income and 25.4% for the lowest) and race (29.9% in whites and 24.3% in blacks). Conclusions: There has been a significant increase in the percentage of stage I lung cancer at diagnosis from 2010 to 2017 which occurred mostly in NSCLC. Disparities in diagnosis and access to treatment may account for the differences in the percentage of patients with stage I among selected demographic populations. The staging trends and recent treatment improvements may lead to better survival for lung cancer. [Table: see text]
A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian, and colorectal cancer susceptibility genes.
Authors: Sukh Makhnoon, Brooke Levin, Megan Ensinger, Kristin Mattie, Robert Joseph Volk, Zhongming Zhao, Tito R. Mendoza, Sanjay Shete, Laila Samiian, Generosa Grana, Andrew V. Grainger, Banu Arun, Brian Shirts, Susan K. Peterson
Journal: Journal of Clinical Oncology (2022)

10512 Background: Up to 10% of all cancers are attributable to germline mutations and identifying mutation carriers is critical for cancer prevention. Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) with unknown impact on health, which can be clarified through reclassification. However, there is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, racial/ethnic differences, and the proportion of patients who undergo cancer preventive healthcare management as a result of VUS reclassification. Methods: Retrospective analysis of persons carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer genes who underwent genetic counseling at four geographically dispersed cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019, and followed until 2020. Results: Among 2,715 individuals, 3,261 VUS and 313 P/LP variants were reported and 11% (300/2,715) had a P/LP in addition to VUS. In total, 8.1% of all individuals with VUS experienced reclassifications, 87.1% of which were downgraded to benign or likely benign and 12.9% were upgraded to P/LP. Reclassification rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p &lt; 0.001). The reclassification pattern across genes suggests that VUS in most genes underwent reclassification at a rate proportional to their prevalence in the overall sample and occurred commonly in ATM, BRCA2, BRCA1, and CHEK2. Compared to their prevalence in the sample, reclassification rates were higher for Blacks (13.6% vs 19.0%), lower for Asians (6.3% vs 3.5%), and proportional for Whites and Hispanics. Median time to reclassification decreased steadily between 2014 and 2019 from 3.08 to 0.91 years. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals’ clinical managements including prophylactic surgeries and intensive screenings for cancer prevention and early detection. Conclusions: In this large multisite study, VUS reclassification changed clinical management for 0.4% of all individuals. VUS reclassification may alter clinical management, has implications for precision cancer prevention, and highlights the need for standardized clinical practice guidelines and policies for returning reclassified results to patients.
Zebrafish Models of Cardiac Disease: From Fortuitous Mutants to Precision Medicine
Authors: Juan Manuel González-Rosa
Journal: Circulation Research (2022)

Heart disease is the leading cause of death worldwide. Despite decades of research, most heart pathologies have limited treatments, and often the only curative approach is heart transplantation. Thus, there is an urgent need to develop new therapeutic approaches for treating cardiac diseases. Animal models that reproduce the human pathophysiology are essential to uncovering the biology of diseases and discovering therapies. Traditionally, mammals have been used as models of cardiac disease, but the cost of generating and maintaining new models is exorbitant, and the studies have very low throughput. In the last decade, the zebrafish has emerged as a tractable model for cardiac diseases, owing to several characteristics that made this animal popular among developmental biologists. Zebrafish fertilization and development are external; embryos can be obtained in high numbers, are cheap and easy to maintain, and can be manipulated to create new genetic models. Moreover, zebrafish exhibit an exceptional ability to regenerate their heart after injury. This review summarizes 25 years of research using the zebrafish to study the heart, from the classical forward screenings to the contemporary methods to model mutations found in patients with cardiac disease. We discuss the advantages and limitations of this model organism and introduce the experimental approaches exploited in zebrafish, including forward and reverse genetics and chemical screenings. Last, we review the models used to induce cardiac injury and essential ideas derived from studying natural regeneration. Studies using zebrafish have the potential to accelerate the discovery of new strategies to treat cardiac diseases.